PROJECT 4: Resistance and relapse in Chronic Myeloid Leukemia Chronic myeloid leukemia (CML) poses a clinical dilemma in optimizing treatment strategy. Transplantation is curative in CML, but is associated with considerable morbidity and mortality. The tyrosine kinase inhibitor (TKI) imatinib has become an attractive "first line" agent for CML. Use of imatinib in newly .diagnosed CP CML yields complete cytogenetic remissions in >75% of cases, nonetheless primary resistance occurs in -20% of chronic phase cases treated with imatinib, and relapse occurs at a rate of ~4%/year. Patients who relapse, especially those with Abl point mutations, appear to have a more virulent clinical course than expected, and often progress to advanced phase. Studies from our group have shown that the molecular "profile" of CML patients who obtain Abl mutations is similar to advanced phase disease. Moreover, patients on imatinib who are transplanted while still in chronic phase but who exhibit imatinib resistance have a surprisingly poor transplant outcome. These findings underscore the need to search for better predictors of response to imatinib, a better understanding of the mechanisms of response and progression in CML, and more information about how these molecular markers of response and progression impact on transplantation outcomes. Thus in Specific Aim 1, we will determine genetics of TKI response and resistance in CML. In Specific Aim 2, we will study the association of global and Abl point mutations in CML. Lastly, in Specific Aim 3 we will evaluate how TKI treatment affects transplant outcomes. We expect these studies will provide a better understanding of why CML patients respond and relapse. We expect this will lead to better diagnostic tests that can predict response, as well as giving insights to novel treatment approaches and pathways to overcome resistance and treat relapse. Moreover, the understanding of how imatinib influences transplant outcomes is a central unanswered question in treating CML, and this project should shed light on this question and the biology underlying it. While these studies are focused on CML, the principal of understanding the biology behind the central question of "who and when should we transplant?" should be applicable to most hematological malignancies. Relevance to Public Health: This project addresses the issue of tailoring therapy to an individual's specific disease. Thus, we will discover the biology of why some cases of CML respond to imatinib, and develop tests to use on patients to predict what therapy will be most effective. While this project is specific to CML, the general strategy of understanding the genetics that determine disease progression and response to therapy should be translatable to many other types of cancer.